CN111793038A - Environment-friendly preparation method of substituted oxazole compound - Google Patents
Environment-friendly preparation method of substituted oxazole compound Download PDFInfo
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- CN111793038A CN111793038A CN201910276111.8A CN201910276111A CN111793038A CN 111793038 A CN111793038 A CN 111793038A CN 201910276111 A CN201910276111 A CN 201910276111A CN 111793038 A CN111793038 A CN 111793038A
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- aryl phosphine
- substituted
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- -1 oxazole compound Chemical class 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 38
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 20
- 150000001412 amines Chemical class 0.000 claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 42
- 239000012074 organic phase Substances 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 16
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 10
- 229960001701 chloroform Drugs 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 150000002916 oxazoles Chemical class 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- SPKBYIYIZQARNX-UHFFFAOYSA-N 1-bis(4-methylphenyl)phosphoryl-4-methylbenzene Chemical compound C1=CC(C)=CC=C1P(=O)(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 SPKBYIYIZQARNX-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims 1
- ZFJMTDFOGDGPTF-UHFFFAOYSA-N phosphanium;chloride;hydrochloride Chemical compound P.Cl.Cl ZFJMTDFOGDGPTF-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 16
- 239000000047 product Substances 0.000 abstract description 11
- 239000002351 wastewater Substances 0.000 abstract description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 6
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 abstract description 5
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 abstract description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 abstract description 4
- 239000004471 Glycine Substances 0.000 abstract description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 4
- 239000011574 phosphorus Substances 0.000 abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000010410 layer Substances 0.000 description 19
- PQRKGFMROBZFIM-UHFFFAOYSA-N ethyl 5-ethoxy-4-methyl-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC(C)=C(OCC)O1 PQRKGFMROBZFIM-UHFFFAOYSA-N 0.000 description 12
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- FWAZRRQVOCUISD-UHFFFAOYSA-N 5-methoxy-4-methyl-1,3-oxazole Chemical compound COC=1OC=NC=1C FWAZRRQVOCUISD-UHFFFAOYSA-N 0.000 description 8
- 238000007127 saponification reaction Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000006114 decarboxylation reaction Methods 0.000 description 6
- ONGHDUMHFLKAII-UHFFFAOYSA-N methyl 5-methoxy-4-methyl-1,3-oxazole-2-carboxylate Chemical compound COC(=O)C1=NC(C)=C(OC)O1 ONGHDUMHFLKAII-UHFFFAOYSA-N 0.000 description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000011726 vitamin B6 Substances 0.000 description 3
- 235000019158 vitamin B6 Nutrition 0.000 description 3
- 229940011671 vitamin b6 Drugs 0.000 description 3
- FWPDSAJKWKRRJD-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole Chemical compound CCOC=1OC=NC=1C FWPDSAJKWKRRJD-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- WZWPVIAZPSGFHJ-UHFFFAOYSA-N ethyl 5-ethoxy-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(OCC)O1 WZWPVIAZPSGFHJ-UHFFFAOYSA-N 0.000 description 2
- YMYCSXUJKPZHKK-UHFFFAOYSA-N ethyl 5-ethoxy-4-phenyl-1,3-oxazole-2-carboxylate Chemical compound CCOC1=C(N=C(O1)C(=O)OCC)C2=CC=CC=C2 YMYCSXUJKPZHKK-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- ROBXZHNBBCHEIQ-UHFFFAOYSA-N ethyl 2-aminopropanoate Chemical compound CCOC(=O)C(C)N ROBXZHNBBCHEIQ-UHFFFAOYSA-N 0.000 description 1
- LWYAOXMPTVOERN-UHFFFAOYSA-N ethyl 2-formamidopropanoate Chemical compound CCOC(=O)C(C)NC=O LWYAOXMPTVOERN-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides an environment-friendly preparation method of a substituted oxazole compound, which comprises the steps of taking N-substituted formyl-alpha-substituted glycine ester as a starting raw material, and carrying out cyclization reaction under the action of a dehydrating agent (a combination of trisubstituted aryl phosphine dichloride, trisubstituted aryl phosphine dichloride and an acyl chloride reagent or a combination of trisubstituted aryl phosphine oxide and an acyl chloride reagent) and organic amine to obtain the substituted oxazole compound. The obtained substituted oxazole compound can be further saponified and decarboxylated to obtain a medical intermediate 4-substituent-5-substituent oxyoxazole. The by-product trisubstituted aryl phosphine oxide in the reaction process can be recycled, so that the cost is reduced; the method does not use phosphorus oxychloride and phosphorus pentoxide dehydrating agents which are high in price and large in preparation process wastewater quantity, does not need high-temperature cyclization reaction, and is simple in process, simple and convenient to operate, free of phosphorus-containing wastewater discharge in the process, green, environment-friendly and low in cost; high atom economy, high yield and purity of target products and suitability for industrial application.
Description
Technical Field
The invention relates to an environment-friendly preparation method of a substituted oxazole compound, belonging to the technical field of pharmaceutical biochemical industry.
Background
Oxazole compounds are important intermediates for preparing substances with life activity, for example, 4-methyl-5-alkoxy oxazole is an important intermediate for synthesizing vitamin B6. Vitamin B6 is one of essential vitamins and plays a key role in the growth process of animals and human bodies, so that the vitamin B6 is widely applied to the fields of medicines, foods, feed additives, cosmetics industry and the like.
At present, the preparation of oxazole compound 4-methyl-5-alkoxy oxazole (taking 4-methyl-5-ethoxy oxazole as an example) mainly comprises the following two methods:
1. formyl cyclisation process
The literature "J.Am.chem.Soc.2007, 129, 4440-4455" and the literature "European Journal of medicinal Chemistry 62(2013) 486-487" are obtained by preparing ethyl N-formyl-2-aminopropionate through formylation by using ethyl 2-aminopropionate and then performing cyclization through the action of phosphorus pentoxide or other dehydrating agents. The preparation method consumes a large amount of phosphorus pentoxide through cyclization, has large wastewater amount, low yield and high cost, and is not beneficial to industrial amplification.
2. Oxalyl compound cyclization method
Chinese patent documents CN86101512A, CN102321043A and CN103435568A and the document 'Chinese medicine industry journal 2009,40(2)81-82, 96' take oxalyl as raw material, and prepare corresponding oxazole compound through cyclization; the preparation method specifically comprises the steps of taking L-alanine, excessive oxalic acid, ethanol and benzene as raw materials, refluxing and carrying water to prepare N-ethoxy oxalyl-L-alanine ethyl ester, cyclizing by phosphorus oxychloride-organic alkali to obtain an oxazole compound, and hydrolyzing and decarboxylating to prepare the 4-methyl-5-ethoxy oxazole. The method has the advantages of complex preparation process, high energy consumption, large amount of wastewater, high content of waste salt, poor atom economy, no contribution to environmental protection and high product cost, and needs to use a dehydrating agent such as phosphorus oxychloride for ring closure.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides an environment-friendly preparation method of a substituted oxazole compound. According to the method, N-substituted formyl-alpha-substituted glycine ester is used as an initial raw material, easily-obtained tri-substituted aryl phosphine dichloride, a combination of tri-substituted aryl phosphine dichloride and an acyl chloride reagent or a combination of tri-substituted aryl phosphine oxide and an acyl chloride reagent is used as a dehydrating agent to prepare the substituted oxazole compound, and the by-product tri-substituted aryl phosphine oxide can be recycled, so that the cost is reduced. The method does not use phosphorus oxychloride and phosphorus pentoxide dehydrating agents which are high in price and large in preparation process wastewater quantity, does not need high-temperature cyclization reaction, and is simple in process, simple and convenient to operate, free of phosphorus-containing wastewater discharge in the process, green, environment-friendly and low in cost; high atom economy, high yield and purity of target products and suitability for industrial application.
Description of terms:
a compound of formula I: substituted oxazole compounds, i.e. 4-R2substituent-5-R1Substituent oxy-2-R3A substituent oxazole;
a compound of formula II: N-R3Substituent formyl-alpha-R2A substituent glycine ester;
a compound of formula III: 4-R2substituent-5-R1Substituent oxyoxazole-2-carboxylate;
a compound of formula IV: 4-R2substituent-5-R1A substituent oxyoxazole.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
an environment-friendly preparation method of a substituted oxazole compound, comprising the steps of:
in a solvent A, under the action of a dehydrating agent and organic amine, a compound shown in a formula II is subjected to cyclization reaction to prepare a substituted oxazole compound (I); the dehydrating agent is a combination of trisubstituted aryl phosphine dichloride, trisubstituted aryl phosphine dichloride and acyl chloride reagent or a combination of trisubstituted aryl phosphine oxide and acyl chloride reagent;
wherein in the structural formula of the compound of the formula II, R1Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r2Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r3is-COOR, -CH2COOR or-CH2CH2COOR, wherein R is alkyl.
Preferably, the solvent A is one or a combination of dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether, n-heptane, xylene, chlorobenzene, benzene, toluene, dimethyl sulfoxide, trichloromethane, trichloroethane or dichloroethane; the mass ratio of the solvent A to the compound shown in the formula II is (0.5-12.0) to 1; preferably, the mass ratio of the solvent A to the compound of the formula II is (3.0-10.0): 1.
According to the invention, when the dehydrating agent is the combination of the tri-substituted aryl phosphine oxide and the acyl chloride reagent, the tri-substituted aryl phosphine oxide and the acyl chloride reagent can generate the tri-substituted aryl phosphine dichloride in situ, and then the dehydrating agent further plays a role in dehydration.
According to the invention, the tri-substituted aryl phosphine oxide is preferably of the formula Ar3PO, wherein Ar has a structure shown as formula V below; the structural formula of the tri-substituted aryl phosphine dichloride is Ar3PCl2Wherein Ar has a structure represented by formula V below;
wherein in the structural formula shown in the formula V, m is 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10) or chloro; preferably, R4Is hydrogen. The structural formula shown in formula V represents: with m radicals R4Respectively arbitrarily connected with six carbon atoms of a benzene ring.
Preferably, the trisubstituted aryl phosphine oxide is triarylphosphine oxide or tris (4-methylphenyl) phosphine oxide and the trisubstituted aryl phosphine dichloride is triarylphosphine dichloride.
Preferably, according to the invention, when the dehydrating agent is a trisubstituted aryl phosphine dichloride, the molar ratio of the trisubstituted aryl phosphine dichloride to the compound of formula II is (0.01-5.0): 1; preferably, the molar ratio of the trisubstituted aryl phosphine dichloride to the compound of formula II is (0.1-1.5): 1; when the dehydrating agent is the combination of the tri-substituted aryl phosphine oxide and the acyl chloride reagent, the molar ratio of the acyl chloride reagent to the compound shown in the formula II is (0.1-2.0):1, and the molar ratio of the tri-substituted aryl phosphine oxide to the compound shown in the formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted aryl phosphine oxide to the compound of formula II is (0.1-1.5): 1; when the dehydrating agent is the combination of the tri-substituted aryl phosphine dichloride and the acyl chloride reagent, the molar ratio of the acyl chloride reagent to the compound shown in the formula II is (0.1-2.0):1, and the molar ratio of the tri-substituted aryl phosphine dichloride to the compound shown in the formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted aryl phosphine dichloride to the compound of formula II is (0.1-1.5): 1.
Preferably, according to the invention, the acid chloride reagent is sulfuryl chloride, thionyl chloride, oxalyl chloride, carbonyl chloride, phosgene, diphosgene or triphosgene; preferably phosgene or triphosgene.
Preferably, according to the invention, the acid chloride reagent is added to the system in a dropwise manner.
According to a preferred embodiment of the invention, the organic amine is a trialkylamine and the alkyl group has the general formula CnH2n+1(1 ≦ n ≦ 10); preferably, the alkyl group is a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an isobutyl group or an n-butyl group, and more preferably an ethyl group, an n-propyl group or an n-butyl group; the molar ratio of the organic amine to the compound of the formula II is (1.8-4.0) to 1; preferably, the molar ratio of the organic amine to the compound of the formula II is (2.0-3.0): 1.
According to the invention, the compound of the formula II is preferably one or the combination of more than two of N-ethoxy oxalyl glycine ethyl ester, N-ethoxy oxalyl-alpha-alanine ethyl ester, N-ethoxy oxalyl glycine methyl ester, N-methoxy oxalyl-alpha-alanine methyl ester, N-ethoxy oxalyl-alpha-phenyl glycine ethyl ester or N-ethoxy oxalyl-alpha-alanine methyl ester.
Preferably, according to the invention, the cyclization reaction temperature is 10-80 ℃; preferably, the cyclization reaction temperature is 30-75 ℃. The cyclization reaction time is 0.5-10 hours.
According to the invention, the compound of formula II is preferably subjected to cyclization reaction to obtain a reaction solution, and the post-treatment method of the obtained reaction solution comprises the following steps: adding water into the obtained reaction liquid, layering, extracting the obtained water layer by using a solvent A, and combining organic phases to obtain a water phase and an organic phase; distilling the organic phase at normal pressure to recover the solvent A, and then distilling the organic phase at reduced pressure to obtain a substituted oxazole compound (I); the obtained water phase or the residue of reduced pressure distillation contains trisubstituted aryl phosphine oxide, and the trisubstituted aryl phosphine oxide can be prepared by reacting with acyl chloride reagent to be used as a dehydrating agent or directly recycled to be used as the dehydrating agent; the obtained water phase can be neutralized by sodium hydroxide and distilled to recover organic amine.
According to the method, organic amine is used as an acid-binding agent to generate organic amine hydrochloride with byproduct hydrogen chloride in the reaction process, then sodium hydroxide and the organic amine hydrochloride are used for neutralization, and finally, the organic amine is recovered and the byproduct sodium chloride is produced.
According to the invention, the substituted oxazole compound (I) can be further prepared into the following oxazole medical intermediate compound formula IV according to the prior art.
According to the invention, the substituted oxazole compound (I) can be used for preparing the compound shown in the formula III through saponification reaction under the action of alkali; then preparing a compound shown in the formula IV by decarboxylation reaction under an acidic condition;
wherein, in the structural formula of the compound shown in the formula III, a substituent R1、R2And a substituent R in the structural formula of a compound shown in a formula II1、R2Similarly, M is an alkali metal and x is 0, 1 or 2, wherein x is 0 meaning that COOM is directly attached to the oxazole ring; in the structural formula of the compound shown in the formula IV, a substituent R1、R2And a substituent R in the structural formula of a compound shown in a formula II1、R2The same is true.
According to the invention, the saponification, the base used and the decarboxylation can be carried out according to the known art.
Preferably, the alkali is an alkali metal hydroxide aqueous solution with the mass concentration of 20-30%; the alkali metal is preferably sodium or potassium; the molar ratio of the alkali to the substituted oxazole compound (I) is 1-1.5: 1; the saponification reaction temperature is 20-30 ℃. The saponification reaction time is 10-60 minutes.
Preferably, the acidic condition is that the pH value of the system is adjusted to be 1-2 by using an acid aqueous solution with the mass concentration of 20-35%; the decarboxylation reaction temperature is 50-70 ℃. The decarboxylation reaction time is 10-60 minutes.
Preferably, the preparation of the compound of formula iv comprises the steps of: performing cyclization reaction on a compound of a formula II to obtain a reaction solution, adding water into the obtained reaction solution, layering, extracting an obtained water layer by using a solvent A, combining organic phases, and adding alkali into the organic phases to perform saponification reaction; and after the reaction is finished, layering, washing the obtained organic layer with water, combining water layers, adding an aqueous solution of acid into the obtained aqueous layer which is a solution containing the compound shown in the formula III, and performing deacidification reaction to obtain the compound shown in the formula IV. After the compound shown in the formula IV is separated, the residual water phase or organic phase contains the trisubstituted aryl phosphine oxide, and the trisubstituted aryl phosphine dichloride prepared by the method and an acyl chloride reagent can be used as a dehydrating agent or directly recycled as the dehydrating agent.
The reaction route of the method is as follows:
wherein in the structural formula of the compound of the formula II, R1Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r2Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r3is-COOR, -CH2COOR or-CH2CH2COOR, wherein R is alkyl. R in the structural formula of the compound of formula I1、R2、R3R in the structural formula of the compound of the formula IV1、R2Are all consistent with the structural formula of the compound shown in the formula II.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel environment-friendly method for preparing a substituted oxazole compound by cyclization; taking N-substituted formyl-alpha-substituted glycine ester (II) as an initial raw material, and reacting a dehydrating agent and organic amine to obtain a substituted oxazole compound (I) by using a combination of trisubstituted aryl phosphine dichloride, trisubstituted aryl phosphine dichloride and an acyl chloride reagent or a combination of trisubstituted aryl phosphine oxide and an acyl chloride reagent as the dehydrating agent. The obtained substituted oxazole compound (I) can be prepared into 4-substituent-5-substituent oxyoxazole (IV) through saponification reaction and decarboxylation reaction according to the prior art.
2. The whole reaction process of the invention can be understood as follows: removing one molecule of water from the compound shown in the formula II through cyclization reaction, reacting the water with tri-substituted aryl phosphine dichloride to generate tri-substituted aryl phosphine oxide and two molecules of hydrogen chloride, and reacting the two molecules of hydrogen chloride with acid-binding agent organic amine to generate organic amine hydrochloride. The dehydrating agent used in the method is a combination of trisubstituted aryl phosphine dichloride, trisubstituted aryl phosphine dichloride and acyl chloride reagent or a combination of trisubstituted aryl phosphine oxide and acyl chloride reagent; when the dehydrating agent is the combination of the trisubstituted aryl phosphine dichloride and the acyl chloride reagent, the trisubstituted aryl phosphine dichloride after the dehydration reaction is converted into the trisubstituted aryl phosphine oxide, and the trisubstituted aryl phosphine oxide and the acyl chloride reagent react in situ to generate the trisubstituted aryl phosphine dichloride which can continuously participate in the dehydration reaction; when the dehydrating agent is the combination of the tri-substituted aryl phosphine oxide and the acyl chloride reagent, the acyl chloride reagent enables the tri-substituted aryl phosphine oxide to generate the tri-substituted aryl phosphine dichloride in situ, and then cyclization reaction is carried out, only sodium chloride and byproduct gas such as sulfur dioxide or carbon dioxide are generated in the process, the generation amount of waste water and waste gas is less, and the method is green and environment-friendly. The dehydrating agent is easy to prepare; the tri-substituted aryl phosphine oxide which is a byproduct in the reaction for preparing the substituted oxazole compound can be recycled, and can be easily and quantitatively converted into the tri-substituted aryl phosphine dichloride, so that the cost is reduced, the cyclic utilization of materials is realized, and the concepts of environmental protection and atom economy are met. The method does not use phosphorus oxychloride and phosphorus pentoxide dehydrating agents which are high in price and large in preparation process wastewater quantity, does not need high-temperature cyclization reaction, and is simple in process, simple and convenient to operate, free of phosphorus-containing wastewater discharge in the process, green, environment-friendly and low in cost.
3. The method has the advantages of high reaction activity, good reaction selectivity, high atom economy, high product yield and purity, high yield of more than 95 percent and high purity of more than 99 percent, and is suitable for industrial application. The obtained substituted oxazole compound (I) can be prepared into an oxazole medical Intermediate (IV) through saponification and decarboxylation according to the prior art.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
In the examples, "%" is a mass percentage unless otherwise specified.
The yields in the examples are all molar yields.
The starting materials and reagents used in the examples are all commercially available products. Raw materials of N-methoxy oxalyl-alpha-alanine methyl ester, N-ethoxy oxalyl glycine ethyl ester and N-ethoxy oxalyl-alpha-phenyl glycine ethyl ester are provided by Shandong Ruihui pharmaceutical industry Co., Ltd, and the GC purity is 99.7%; the raw material N-ethoxy oxalyl-alpha-alanine ethyl ester is provided for new pharmaceutical industry Co.
Performing gas phase detection by using Shimadzu gas chromatograph, wherein the model of the instrument is GC-1020 PLUS; some of the purity was measured by high performance liquid chromatography and is indicated as HPLC.
Example 1: 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole (I)1) Preparation of
Adding 100 g of trichloromethane, 33.3 g (0.1 mol) of triphenyl phosphine dichloride and 21.7 g (0.1 mol) of N-ethoxyoxalyl-alpha-alanine ethyl ester into a 250 ml flask, dropwise adding 20.2 g (0.2 mol) of triethylamine at 20-25 ℃ within 2 hours, reacting at 35-40 ℃ for 1 hour, detecting the reaction of the raw materials, adding 30 g of water, layering, extracting the obtained water layer twice (using 30 g in total) by using the trichloromethane, combining organic phases, distilling the organic phases at normal pressure to recover the trichloromethane, and then distilling under reduced pressure to obtain 18.8 g of 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole, wherein the yield is 94.4%, and the GC purity is 99.9%; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydrating agent.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(CDCl3,,ppm)：
4.28(q,2H),4.31(q,2H),2.07(s,3H),1.36(t,3H),1.33(t,3H)。
example 2: 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole (I)1) Preparation of
Adding 100 g of toluene, 3.4 g (0.01 mol) of triphenyl phosphine dichloride, 21.7 g (0.1 mol) of N-ethoxyoxalyl-alpha-alanine ethyl ester, 20.8 g (0.206 mol) of triethylamine, dropwise adding a solution of 9.9 g (0.1 mol) of phosgene and 50 g of toluene at the temperature of 25-30 ℃, completing dropwise adding within 2 hours, reacting at the temperature of 65-70 ℃ for 1 hour, detecting that the raw materials are reacted, adding 30 g of water, layering, extracting an obtained water layer twice (using 30 g in total) by using the toluene, combining organic phases, distilling the organic phases at normal pressure to recover the toluene, and then distilling under reduced pressure to obtain 18.9 g of 4-methyl-5-ethoxy-2-ethoxycarbonyl oxazole, wherein the yield is 94.9 percent, and the GC purity is 99.9 percent; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydrating agent.
Example 3: 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole (I)1) Preparation of
Adding 100 g of toluene, 27.8 g (0.1 mol) of triphenylphosphine oxide and 21.7 g (0.1 mol) of N-ethoxyoxalyl-alpha-alanine ethyl ester into a 500 ml four-neck flask, dropwise adding a solution of 100 g of toluene and 9.9 g (0.033 mol) of triphosgene into the 500 ml four-neck flask within 2 hours at 20-25 ℃, simultaneously dropwise adding 24.3 g (0.24 mol) of triethylamine, reacting at 45-50 ℃ for 1 hour after double dropwise adding, detecting the reaction completion of raw materials, adding 30 g of water, layering, extracting the obtained water layer twice (using 30 g in total) by using toluene, combining organic phases, distilling the organic phases at normal pressure to recover the toluene, and then distilling under reduced pressure to obtain 19.1 g of 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole with the yield of 96 percent and the purity of GC of 99.9 percent; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydrating agent.
Example 4: 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole (I)1) Preparation (with recovered triphenylphosphine oxide)
The residue obtained after recovering 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole by distillation in example 3 was mainly triphenylphosphine oxide and was repeatedly used as a dehydrating agent; dissolving 100 g of toluene, adding the dissolved solution into a 500 ml four-neck flask, adding 21.7 g (0.1 mol) of N-ethoxyoxalyl-alpha-alanine ethyl ester, 24.4 g (0.24 mol) of triethylamine, adding a solution of 100 g of toluene and 9.9 g (0.033 mol) of triphosgene into the 500 ml four-neck flask at 25-30 ℃ within 2 hours, reacting at 45-50 ℃ for 1 hour, detecting the reaction of the raw materials, adding 30 g of water, layering, extracting the obtained water layer twice with toluene (using 30 g in total), combining organic phases, distilling the organic phases at normal pressure to recover toluene, and then distilling under reduced pressure to obtain 19.3 g of 4-methyl-5-ethoxy-2-ethoxycarbonyl oxazole, wherein the yield is 96.9 percent and the GC purity is 99.9 percent; the main component of the residue after reduced pressure distillation is triphenylphosphine oxide which can be repeatedly used as a dehydrating agent.
Example 5: 4-methyl-5-methoxy-2-methoxycarbonyloxazole (I)2) And 4-methyl-5-methoxy oxazole (IV)2) Preparation of
A500 ml four-neck flask is added with 80 g xylene, 27.8 g (0.1 mol) triphenylphosphine oxide, 18.9 g (0.1 mol) N-methoxy oxalyl-alpha-alanine methyl ester, 20.8 g (0.206 mol) triethylamine, a mixed solution of 60 g xylene and 9.9 g (0.1 mol) phosgene is added into the 500 ml four-neck flask at 30-35 ℃ within 2 hours, the mixture reacts at 35-40 ℃ for 1 hour, after the reaction of the raw materials is detected, 30 g water layers are added, the water layers are extracted twice by xylene (30 g is used in total), organic phases are combined, 16.1 g of 4-methyl-5-methoxy-2-methoxycarbonyloxazole is obtained by GC detection, and the yield is 94%.
Adding 20 g of 25% sodium hydroxide aqueous solution into the organic phase, stirring for 30 minutes at room temperature, layering, washing the organic phase for 2 times (30 g of water each time) by using water, and recycling the obtained organic phase as a dehydrating agent; the water layers are combined, 24.7 g of 31 percent hydrochloric acid is added, the pH value is adjusted to be 1.5, the temperature is increased to 60 ℃, the temperature is kept for 30 minutes, the mixture is neutralized to be neutral, reduced pressure distillation is carried out, 10.1 g of 4-methyl-5-methoxy oxazole is obtained, the yield is 89.3 percent by the N-methoxy oxalyl-alpha-alanine methyl ester, and the GC purity is 99.9 percent.
The nuclear magnetic data of the obtained product 4-methyl-5-methoxy oxazole are as follows:
1H NMR(CDCl3,,ppm)：
7.33(s,1H),3.89(s,3H),1.99(s,3H)。
example 6: 4-methyl-5-methoxy-2-methoxycarbonyloxazole (I)2) Preparation (with recovered triphenylphosphine oxide)
The residue obtained after recovering 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole by distillation in example 3 was mainly triphenylphosphine oxide and was repeatedly used as a dehydrating agent; dissolving 100 g of toluene, adding the dissolved solution into a 500 ml four-neck flask, adding 18.9 g (0.1 mol) of N-methoxy oxalyl-alpha-alanine methyl ester, 20.8 g (0.206 mol) of triethylamine, adding a solution of 60 g of toluene and 9.9 g (0.1 mol) of phosgene into the 500 ml four-neck flask at the temperature of between 20 and 25 ℃ within 2 hours, reacting at the temperature of between 35 and 40 ℃ for 1 hour, detecting the reaction completion of raw materials, adding 30 g of water layers, extracting the water layers twice by using the toluene (30 g in total), combining organic phases, distilling the organic phases at normal pressure to recover the toluene, and then distilling under reduced pressure to obtain 16.5 g of 4-methyl-5-methoxy-2-methoxycarbonyl oxazole with the yield of 96.4%.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(CDCl3,,ppm)：
3.89(s,3H),3.85(s,3H),2.07(s,3H)
example 7: 4-methyl-5-methoxy-2-methoxycarbonyloxazole (I)2) Preparation of
Adding 80 g of cyclohexane, 32 g (0.1 mol) of tris (4-methylphenyl) phosphine oxide, 18.9 g (0.1 mol) of N-methoxyoxalyl-alpha-alanine methyl ester, 28.9 g (0.202 mol) of tri-N-propylamine into a 500 ml four-neck flask, dropwise adding a mixed solution of 11.9 g (0.1 mol) of thionyl chloride and 60 g of cyclohexane at the temperature of 20-25 ℃ within 2 hours, reacting at the temperature of 60-65 ℃ for 1 hour after the dropwise adding is finished, detecting that the raw materials react completely, adding 30 g of water layer, extracting the water layer twice (using 30 g in total) by using cyclohexane, combining organic phases, washing the organic phase once by using 30 g of aqueous solution, layering to obtain an aqueous phase and an organic phase, combining the aqueous phase (using part of water indiscriminately), using the tris (4-methylphenyl) phosphine oxide in the aqueous phase, distilling the obtained organic phase under normal pressure to recover cyclohexane, and then distilling under reduced pressure to obtain 15.6 g of 4-methyl-5-methoxy-2-methoxycarbonyloxazole, the yield was 91.2% and the GC purity was 99.2%.
Example 8: 4-phenyl-5-ethoxy-2-ethoxycarbonyloxazole (I)3) Preparation of
A500 ml four-necked flask was charged with 100 g of toluene, 32 g (0.1 mol) of tris (4-methylphenyl) phosphine oxide, 27.9 g (0.1 mol) of ethyl N-ethoxyoxalyl-. alpha. -phenylglycine, 25.3 g (0.25 mol) of triethylamine, and a solution of 10.1 g (0.034 mol) of triphosgene and 50 g of toluene was added dropwise at 25 to 30 ℃ for 2 hours, followed by reaction at 45 to 50 ℃ for 1 hour, detecting the reaction of the raw materials, adding 30 g of water for layering, extracting a water layer by using toluene (30 g in total), combining organic phases, washing the organic phase once by using 30 g of aqueous solution, layering to obtain a water phase and an organic phase, combining the water phases, distilling the obtained organic phase under reduced pressure to recover the toluene, then carrying out reduced pressure distillation to obtain 22.3 g of 4-phenyl-5-ethoxy-2-ethoxycarbonyl oxazole with the yield of 85.3 percent.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(CDCl3,,ppm)：
7.6(d,2H),7.4-7.5(m,3H),4.27(q,2H),4.31(q,2H),1.35(t,3H),1.33(t,3H)
example 9: 5-ethoxy-2-ethoxycarbonyloxazole (I)4) Preparation of
A500 ml four-neck flask is added with 80 g of toluene, 27.8 g (0.1 mol) of triphenylphosphine oxide, 20.3 g (0.1 mol) of ethyl N-ethoxyoxalyl glycinate, 22.2 g (0.22 mol) of triethylamine, a solution of 10.0 g (0.1 mol) of phosgene and 50 g of toluene is dripped between 25 ℃ and 30 ℃ after 2 hours of dripping, the reaction is carried out for 1 hour at 50 ℃ to 55 ℃, 30 g of water layer is added after the detection of the reaction of the raw materials, the water layer is extracted by toluene (30 g in total), organic phases are combined, the organic phase is washed by 30 g of water solution once, water phase and organic phase are obtained by layering, the water phase is combined, the obtained organic phase is decompressed and distilled to recover toluene, then decompressed and distilled to obtain 17.6 g of 5-ethoxy-2-ethoxycarbonyloxazole, the yield is 95.1 percent, and the GC purity is 99.9 percent.
The nuclear magnetic data of the product obtained are as follows:
1H NMR(CDCl3,,ppm)：
6.81(s,1H),4.29(q,2H),4.32(q,2H),1.35(t,3H),1.32(t,3H)。
comparative example: 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole (I)1) Preparation of
100 g of trichloromethane, 33.3 g (0.1 mol) of triphenylphosphine dichloride and 21.7 g (0.1 mol) of N-ethoxyoxalyl-alpha-alanine ethyl ester are added into a 250 ml flask, 20.2 g (0.2 mol) of triethylamine is added dropwise at 0-10 ℃ within 2 hours, then the mixture reacts at 0-10 ℃ for 1 hour, 30 g of water is added for layering, the obtained water layer is extracted twice by trichloromethane (30 g in total), organic phases are combined and distilled at normal pressure to recover the trichloromethane, and then the mixture is distilled under reduced pressure to obtain 15.3 g of 4-methyl-5-ethoxy-2-ethoxycarbonyloxazole, wherein the yield is 76.6 percent, and the GC purity is 98.3 percent.
As can be seen from this comparative example, when the reaction temperature is low, the conversion is incomplete and the product yield is low.
Claims (10)
1. An environment-friendly preparation method of a substituted oxazole compound, comprising the steps of:
in a solvent A, under the action of a dehydrating agent and organic amine, a compound shown in a formula II is subjected to cyclization reaction to prepare a substituted oxazole compound (I); the dehydrating agent is a combination of trisubstituted aryl phosphine dichloride, trisubstituted aryl phosphine dichloride and acyl chloride reagent or a combination of trisubstituted aryl phosphine oxide and acyl chloride reagent;
wherein in the structural formula of the compound of the formula II, R1Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r2Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10), an aromatic group, or a substituted aromatic group; r3is-COOR, -CH2COOR or-CH2CH2COOR, wherein R is alkyl.
2. An environmentally friendly process for the preparation of substituted oxazole compounds according to claim 1 comprising one or more of the following conditions:
a. the solvent A is one or a combination of dichloromethane, chloroform, normal hexane, cyclohexane, petroleum ether, normal heptane, xylene, chlorobenzene, benzene, toluene, dimethyl sulfoxide, trichloromethane, trichloroethane or dichloroethane; the mass ratio of the solvent A to the compound shown in the formula II is (0.5-12.0) to 1;
b. the organic amineIs trialkylamine, the alkyl group having the formula CnH2n+1(1 ≦ n ≦ 10); preferably, the alkyl group is a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an isobutyl group or an n-butyl group, and more preferably an ethyl group, an n-propyl group or an n-butyl group; the molar ratio of the organic amine to the compound of the formula II is (1.8-4.0) to 1; preferably, the molar ratio of the organic amine to the compound of the formula II is (2.0-3.0): 1.
3. The environmentally friendly process of claim 1, wherein said trisubstituted aryl phosphine oxide has the structural formula Ar3PO, wherein Ar has a structure shown as formula V below; the structural formula of the tri-substituted aryl phosphine dichloride is Ar3PCl2Wherein Ar has a structure represented by formula V below;
wherein in the structural formula shown in the formula V, m is 1, 2, 3, 4 or 5, R4Is hydrogen, CnH2n+1A group (1 ≦ n ≦ 10) or chloro; preferably, R4Is hydrogen.
4. The environmentally friendly process of preparing a substituted oxazole compound of claim 3 wherein the trisubstituted aryl phosphine oxide is triaryl phosphine oxide or tris (4-methylphenyl) phosphine oxide and the trisubstituted aryl phosphine dichloride is triaryl phosphine dichloride.
5. The environmentally friendly process for the preparation of a substituted oxazole compound of claim 1 wherein when the dehydrating agent is a trisubstituted aryl phosphine dichloride, the molar ratio of trisubstituted aryl phosphine dichloride to the compound of formula ii is (0.01-5.0) 1; preferably, the molar ratio of the trisubstituted aryl phosphine dichloride to the compound of formula II is (0.1-1.5): 1; when the dehydrating agent is the combination of the tri-substituted aryl phosphine oxide and the acyl chloride reagent, the molar ratio of the acyl chloride reagent to the compound shown in the formula II is (0.1-2.0):1, and the molar ratio of the tri-substituted aryl phosphine oxide to the compound shown in the formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted aryl phosphine oxide to the compound of formula II is (0.1-1.5): 1; when the dehydrating agent is the combination of the tri-substituted aryl phosphine dichloride and the acyl chloride reagent, the molar ratio of the acyl chloride reagent to the compound shown in the formula II is (0.1-2.0):1, and the molar ratio of the tri-substituted aryl phosphine dichloride to the compound shown in the formula II is (0.01-5.0): 1; preferably, the molar ratio of the acid chloride reagent to the compound of formula II is (0.3-1):1, and the molar ratio of the trisubstituted aryl phosphine dichloride to the compound of formula II is (0.1-1.5): 1.
6. The environmentally friendly process for the preparation of substituted oxazole compounds of claim 1 wherein the acid chloride reagent is sulfuryl chloride, thionyl chloride, oxalyl chloride, carbonyl chloride, phosgene, diphosgene or triphosgene; preferably phosgene or triphosgene.
7. The environmentally friendly process for the preparation of a substituted oxazole compound of claim 1 wherein the acid chloride reagent is added to the system in a dropwise manner.
8. The environmentally friendly process for preparing substituted oxazole compounds as set forth in claim 1 wherein said compound of formula ii is one or a combination of two or more of ethyl N-ethoxyoxalyl- α -alaninate, methyl N-ethoxyoxalyl- α -alaninate, ethyl N-ethoxyoxalyl- α -phenylglycinate or methyl N-ethoxyoxalyl- α -alaninate.
9. The environmentally friendly process for the preparation of substituted oxazole compounds of claim 1 wherein the ring closure reaction temperature is 10 to 80 ℃; preferably, the cyclization reaction temperature is 30-75 ℃.
10. The environmentally friendly process for the preparation of a substituted oxazole compound according to claim 1 wherein the compound of formula ii is cyclized to obtain a reaction solution and the post-treatment of the reaction solution comprises the steps of: adding water into the obtained reaction liquid, layering, extracting the obtained water layer by using a solvent A, and combining organic phases to obtain a water phase and an organic phase; distilling the organic phase at normal pressure to recover the solvent A, and then distilling the organic phase at reduced pressure to obtain a substituted oxazole compound (I); the obtained water phase or the residue of reduced pressure distillation contains trisubstituted aryl phosphine oxide, and the trisubstituted aryl phosphine oxide can be prepared by reacting with acyl chloride reagent to be used as a dehydrating agent or directly recycled to be used as the dehydrating agent; the obtained water phase can be neutralized by sodium hydroxide and distilled to recover organic amine.
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Denomination of invention: An environmentally friendly preparation method for substituted oxazole compounds Effective date of registration: 20231130 Granted publication date: 20220812 Pledgee: Dongying Branch of China CITIC Bank Co.,Ltd. Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980068537 |